The polymerization of sickle hemoglobin arises from the reduced solubility of concentrated deoxygenated sickle hemoglobin found within intact red blood cells from individuals with sickle cell anemia. We have examined the solubility of hemoglobin S mixtures with hemoglobins A, A2 and F at varying oxygen saturations to determine the extent of hemoglobin S polymerization under physiologic conditions. A detailed analysis of the solubility of mixtures of hemoglobin at various oxygen saturations provides the means to predict the maximum extent of polymerization within the sickle hemoglobin containing erythrocyte. Ultracentrifugation of polymerized hemoglobin mixtures at different ligand concentrations was used to measure directly the equilibrium solubility of sickle hemoglobin mixtures. These measurements indicated that the solubility increases with ligand concentration and the critical oxygen saturation above which no polymer is detected is shifted to lower ligand concentrations as the percent fetal hemoglobin increases. The sparing effect of hemoglobin A2 was comparable to the sparing effect of hemoglobin F. Hemoglobin A and hemoglobin C exhibited similar effects on hemoglobin S polymerization in comparable mixtures. The current study also demonstrates explicitly the polymerization behavior of hemoglobin S and hemoglobin F mixtures at increasing ligand concentrations. The theoretical model based on experimental data of polymerization of hemoglobin mixtures was used to analyze observations obtained from 2674 individuals with sickle cell anemia from the Cooperative Study of Sickle Cell Disease database. These data indicate that during the first twelve years of life, fetal hemoglobin decreased while mean corpuscular hemoglobin concentration increases until adolescence. These changes result in a continuous rise in polymerization tendency during the first twelve years of life. Data obtained from the Parisian Prospective Study on Sickle Cell Disease was sued to determine the variation in fetal hemoglobin and polymerization tendency in children with sickle cell anemia during the first two years of life. These data indicated that 3 of 21 children had a significantly greater predicted polymerization tendency due to early decreases in hemoglobin F. These individuals will be studied prospectively to ascertain the relationship among polymerization tendency and various clinical manifestations of sickle cell disease.